High IFN-γ Production of Individual CD8 T Lymphocytes Is Controlled by CD152 (CTLA-4)

Abstract

CD8 T cell expansion and cytokine production is needed to generate an effective defense against viral invasion of the host. These features of CD8 T lymphocytes are regulated, especially during primary responses, by positive and negative costimulation. We show in this study that surface expression of CD152 is highly up-regulated on activated CD8 T lymphocytes during primary immune responses, suggesting a prominent regulatory role. Indeed, production of the proinflammatory cytokine IFN-γ, but not TNF-α, by CD8 T cells was inhibited by CD152 engagement. The inhibition was regulated independent of proliferation and IL-2 production, but dependent on the quality of the TCR signaling. We show that signals induced by CD152 on activated CD8 T lymphocytes reduce the frequency of IFN-γhigh-expressing cells. Our data also show that in activated CD8 T cells, the CD152-mediated inhibition of cytokine production is more pronounced than inhibition of their proliferation.

A New Role of CTLA-4 on B Cells in Thymus-Dependent Immune Responses In Vivo

“…Since recently, the traditional view of CTLA-4 inhibitory effects on T cell responses was merely attributed to its inhibitory effect of inducing cell cycle arrest (12,34,53). New data now demonstrate that CTLA-4 signaling can indeed down-regulate effector molecules such as IFN-␥ of individual CD8 T cells (35). One or both functions of CTLA-4 mentioned could explain the enhanced Ab production caused by the genetic inactivation of CTLA-4 on B cells (12,34,54,55).…”

“…Surface and intracellular expression of CTLA-4 was detected using immunofluorescent liposomes as described elsewhere (35). Cytometric analyses were performed using a FACSCalibur (BD Biosciences) and CellQuest software (BD Biosciences).…”

The differentiation and plasticity of Tc17 cells are regulated by CTLA-4-mediated effects on STATs

“…Initially, downstream targets of the Tc1 lineage were analyzed to confirm the Tc1 conversion, as it is well established that inhibiting CTLA-4 enhances Tc1 differentiation. 29,35 First, flow cytometric analysis showed that the CTLA-4-crosslinked cells more effectively retained their Tc17 profile, even under Tc1-skewing conditions, compared with the activated control cells (Fig. 5A).…”

“…33,34 Focusing on the major effector cells that eliminate tumors, CTLA-4-deficient CD8 C T cells exhibited increased production of IFNg and granzyme B. 29,35 In a Tc17 milieu, CTLA-4 supports Tc17 differentiation and limits the lineage plasticity of the Tc17 phenotype by inhibiting the expression of central factors of the Tc1 program, namely, IFNg and granzyme B. 36 This indicates that CTLA-4 affects the Tc1 and Tc17 lineage programs.…”

“…[27][28] On CD8 C T cells, it is expressed at particularly high levels and for long period of time. 29 Blockade of CTLA-4 in patients having advanced melanoma is effective as a single agent for antitumor therapy [30][31][32] and is even better in combination with agents that block other inhibitory molecules. 33,34 Focusing on the major effector cells that eliminate tumors, CTLA-4-deficient CD8 C T cells exhibited increased production of IFNg and granzyme B.…”